Mce transport systems of Mycobacterium tuberculosis

描述(申请人提供)：结核分枝杆菌，人类结核病的病原体，感染了大约三分之一的世界人口，每年导致近200万人死亡。治疗现有疾病的新战略和改进疫苗接种方法以防止新的感染，将需要更多地了解这种病原体在宿主体内持续存在并导致疾病的机制。与许多其他细菌病原体不同，结核分枝杆菌主要通过分泌各种复杂的小分子与宿主相互作用。使用一种新的遗传方法，我们已经确定了次生代谢物生物合成途径和大型多亚单位运输系统，它们协同发挥作用，促进细菌在体内的生长和疾病的进展。利用一组缺乏生物合成基因运输系统的结核分枝杆菌突变体，我们将识别介导细菌和宿主之间相互作用的新化合物(目标1)。通过表征这些突变体与宿主巨噬细胞之间改变的相互作用，我们将确定这些系统在感染过程中发挥的特定作用(目标2)，最后，我们将剖析单个转运蛋白组件的结构和功能，以确定毒力特异性适应，以解释这种感染的一些独特生物学(目标3)。

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis, the causative agent of human tuberculosis infects approximately one-third of the world's population and kills nearly two million people each year. New strategies of the treatment of existing disease and improved vaccination methods to prevent new infections will require a greater understanding of the mechanisms used by this pathogen to persist in the host and cause disease. Unlike many other bacterial pathogens, M. tuberculosis interacts with the host largely through the secretion of a wide variety of complex small molecules. Using a new genetic methodology, we have identified secondary metabolite biosynthetic pathways and large multisubunit transport systems that function in concert to promote bacterial growth in vivo and disease progression. Using a panel of M. tuberculosis mutants that lack either transport systems of biosynthetic genes, we will identify the novel compounds that mediate interactions between the bacterium and host (Aim 1). By characterizing the altered interaction between these mutants and the host macrophage, we will determine the the specific roles played by these systems during infection (Aim 2), Finally, we will dissect the structure and functions of individual transporter components to identify virulence-specific adaptations that explain some of the unique biology of this infection (Aim 3).